Method of preparing alkoxymethylene compounds

ABSTRACT

An improvement in the alkoxylation of a compound having a reactive methylene group by contacting said compound with an orthoformic acid trialkyl ester in the presence of a catalyst, the improvement residing in employing at least 1.6 moles of orthoformic acid ester per mole of compound having a reactive methylene group and carrying out the process in the presence of a catalyst of the group of aliphatic carboxylic acids, anhydrides of aliphatic carboxylic acids, aromatic sulphonic acids, alkali metal alcoholates and alkanolamines.

CROSS REFERENCE TO RELATED APPLICATION

This is a continuation-in-part of copending application Ser. No. 825,794of Aug. 9, 1977, entitled Method of Preparing Alkoxymethylene Compound,now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a process for the alkoxylation of compoundshaving reactive methylene groups. More especially, this inventionrelates to the preparation of such alkoxymethylene compounds by reactionof compounds having a reactive methylene group with excess orthoformicacid ester in the presence of a catalyst. This invention is particularlyconcerned with the preparation of alkoxymethylene compounds insubstantially quantitative amounts where the alkoxymethylene compoundsis recovered in high purity.

2. Discussion of the Prior Art

L. Claisen, in "Berichte" 26, 2729 (1893), and Ann. 297, 19 (1897),described the condensation of orthoformic acid esters with compoundscontaining reactive methylene groups in the presence of acetic acidanhydride as catalyst. The mechanism of this reaction was thoroughlystudied by Post, J. Org. Chem. 2, 260 (1937) and by Fuson, J. Org. Chem.11, 194 to 198 (1946).

A description is furthermore given in U.S. Pat. Nos. 2,824,121 of thepreparation of alkyoxymethylene compounds from orthoformic acid triethylesters and compounds containing reactive methylene groups, in thepresence of acetic acid anhydride as catalyst. The preparation of thiscompound in the presence of excess orthoformic acid ester is alsodescribed in U.S. Pat. No. 4,058,553. In this method, carboxylic acidsand their anhydrides as well as Lewis acids must be present as catalystsin order to obtain the desired high transformation together with goodyields.

The first-named methods have the disadvantage that the reactions of thetwo reaction components with one another are incomplete, and numerousby-products form which considerably reduce the yield. The voltatileby-products are, some of them, very difficult to separate bydistillation from the alkoxymethylene compounds. The solid by-productsreduce the yield and make refinement difficult. On this account theeconomical preparation of the pure alkoxymethylene derivatives is madedifficult and in some cases impossible.

In the method of U.S. Pat. No. 4,058,553, the simultaneous use of twodifferent catalysts is disadvantageous. The amount of catalyst isaccordingly relatively great.

It is an object of this invention, therefore, to provide an improvedprocess for the production of such alkoxylated methylene compounds wherethe alkoxylated methylene compounds are obtained in a virtuallyquantitative yield. More especially, it is an object of this inventionto provide an improved process for the production of suchalkoxymethylene compounds which does not require a multi-componentcatalyst system. It is a further object of this invention to providesuch alkoxymethylene compounds especially alkoxymethylene malonic acidderivatives in high yields and in high purity. These and other objectsof this invention become apparent in the following description andclaims.

SUMMARY OF THE INVENTION

Broadly, this invention contemplates an improvement in the process forpreparing an alkoxymethylene malonic acid derivative by reaction of anorthoformic acid ester with a compound containing a reactive methylenegroup, the improvement comprising carrying out the process employing anexcess of orthoformic acid ester and performing the process in thepresence of a catalyst of the group of aliphatic carboxylic acids,anhydrides of aliphtic carboxylic acids and optionally aromatic sulfonicacids, alkali metal alcoholates and alkanolamines. Especiallycontemplated as catalyst is acetic anhydride.

It has been discovered in accordance with the disclosure in said Ser.No. 825,794, the disclosure of which is hereby incorporated herein byreference, that alkoxymethylene malonic acid derivatives can be preparedin virtually quantitative yields by a process which does not requiremulti-component catalyst system if the process is carried out employingan excess of orthoformic acid ester employing a catalyst as named aboveand the alcohol which forms during the process is continuously removed,e.g., by distillation.

In accordance with the invention, the alkoxymethylene malonic acidderivative is formed by reaction of the orthoformic acid ester and themalonic acid derivative having a reactive methylene group employing atleast 1.6 mole of orthoformic acid ester per mole of a compoundpossessing a reactive methylene group. The alcohol that forms during theprocess is preferably removed by distillation as it forms. Preferably,the mole ratio of orthoformic acid ester to malonic acid compoundcontaining reactive methylene group is 1.6 to 6:1. A further excess oforthoformic acid does not bring any economic advantages.

The reaction of the malonic acid derivatives put in is virtuallyquantitative, hardly any by-products being formed. The work-up andpurification of the products obtained is quite simple.

The formation of undesired by-products is almost entirely prevented byuse of excess orthoformic acid esters and by the continuous separationof the alcohol that forms. In addition to its function as a component ofthe reaction, the ortho ester that is present in excess suppresses theformation of by-products that might appreciably reduce the yield.

A catalyst from the group of the aliphatic carboxylic acids or theiranhydrides, aromatic sulfonic acids, alkali metal alcoholates andalkanolamines is preferred. The preferred aliphatic carboxylic acids oranhydrides are those having 2 to 4 carbon atoms. Preferably, aceticanhydride is employed. p-Toluenesulfonic acid and phenolsulfonic acidare cited as examples of aromatic sulfonic acids. Other C₆ -C₁₂ aromaticsulfonic acids can also be employed.

The alcoholate moiety in the alkali alcoholates is preferably one of 1to 4 carbon atoms, the alcohol preferably being an alkanol; thealkanolamines are preferably also alkanolamines of 2 to 4 carbon atoms,such as triethanolamine, ethanolamine, triisopropanolamine, and2-amino-1-butanol. The alkanolamines and alkali metal alcoholates act inamounts of as little as 0.005 moles per mole of compound of activemethylene group, while the other catalysts are used in amounts of 0.03mole and up, per mole of such compound. The maximum is 0.5 mole, but inprinciple one can use large amounts. Preferably, one part of thecatalyst (up to 50% of its total weight) is added before starting thereaction, the other part is added during the reaction, continuously orin several portions.

The use of additional catalysts other than those named, for example,Lewis acids, pursuant to the method of U.S. Pat. No. 4,058,553, isunnecessary.

The malonic acid derivatives which can be used as reactants include, ofcourse, the compounds containing reactive methylene groups disclosed inthe above-cited U.S. Pat. No. 2,824,121. These compounds include malonicacid dinitrile, cyanoacetic acid, acetyl acetone and acetoacetic estersparticularly the methyl and ethyl ester. Thus, particularly contemplatedcompounds for reaction with the orthoformic acid trialkyl ester includecompounds having the following structural formulae. ##STR1## In each ofthe formulae (2) to (4) the --CH₃ --moiety can be replaced by a C₂ H₅--moiety.

Where the reactant possessing the reactive methylene group has an esterfunction the ester function is preferably derived from a C₁ to C₃alcohol. Preferably, the ester group is a C₁ to C₃ alkyl group.Generally speaking, the ester component will be the same ester group ofthe orthoformic acid trialkyl ester which can be C₁ to C₄ carbon atomsalthough methyl and ethyl are preferred. The molar ratio of the reactantpossessing the reactive methylene group to orthoformic acid ester is,broadly speaking, 1:1.6-6.

The reaction temperature is between 90° and 165° C. It is selected suchthat the alcohol that forms can be distilled out. At temperatures above160° C., excessive amounts of undesired compounds form, some of themsolids, which greatly decrease the yield. At lower temperatures thetransformation is poor, or products from which reduce the yield and makeit very difficult or impossible to isolate economically the purealkoxymethylene malonic acid derivatives.

The method can be practiced in a reaction flask which is equipped with amechanical stirrer, a temperature measuring means for the reactionsolution, a dropping funnel, and a fractionation column with condenser,return, and a flask for collecting the alcohol. The process can beconducted batchwise or continuously.

The method is practiced as a rule by heating to ebullition, withstirring, the mixture of malonic acid nitrile, orthoformic acid esterand catalyst in the above-given molar ratio. The alcohol that forms iscontinuously distilled out of the reaction mixture through a column. Theheating of the solution is so regulated that the temperature of thereaction solution is between 90° and 165° C., and, when orthoformic acidtriethyl ester is used, is between 60° and 80° C. at the top of thecondenser. When orthoformic acid trimethylester is used, the temperatureat the top of the condenser is between 55° and 70° C.

The process can be conducted at reduced pressure down to 20 mm Hg and atelevated pressure up to 5 atm. Preferably, the process is conducted atatmospheric pressure.

After the reaction has ended, the unreacted orthformic acid ester isremoved by distillation at reduced pressure and is recycled to the nextbatch. The alkoxymethylene compound remaining in the sump is evaporatedfrom the residue at 0.01 to 2 Torr. After this single distillation italready has a purity which makes it usable in most areas of application.

The products prepared by the present method are intermediates in thepreparation of pharmaceutically effective pyrimidine derivatives, suchas allopurinol, for example. Products of the invention can be convertedto a pharmaceutically effective pyrimidine derivative, such asallopurinol in accordance with the procedure described in German PatentSpecification No. 17 70 099.

It can also be used for other condensation reactions in which thealkoxy- (or carbalkoxy)- groups and nitrile groups of the productsobtained by the claimed reaction, are reacted with amidines or areacompounds or amines.

In order to more fully illustrate the nature of the invention and themanner of practicing the same, the following examples are presented.

EXAMPLES Example 1

A two-liter, four-necked flask is charged with 1332 g (9 moles) oforthoformic acid triethyl ester, 198 g (3 moles) of malonic aciddinitrileand 4 g of acetic acid anhydride. With vigorous stirring, thesolution is heated to ebullition. At about 110° C. sump temperature,alcohol begins to distil out through the top of the column. During thecourse of the reaction, approximately 8 g of acetic acid anhydride isfed in continuously, and the heating of the reaction mixture and thereflux flow are so regulated that the temperature at the top of thecondenser is between 75° and 79° C. The condensed distillate iscollectedand consists substantially of ethanol, acetic acid ethyl ester,formic acidethyl ester and a small amount of orthoformic acid triethylester. During the reaction the sump temperature rises slowly to 130 to140 degrees C. After 2 to 3 hours the reaction has ended. The unreactedorthoformic acid triethyl ester is distilled out through the column andis fed back to the next batch. Then ethoxymethylene malonic aciddinitrile is separated from the remainder through a simple distillationbridge at 0.1 to 0.02 Torr. Inthis manner, 361 g of ethoxymethylenemalonic acid dinitrile is obtained, with a melting point of 64° C. and apurity of better than 99%. This corresponds to a yield of 98.7% withrespect to the malonic acid dinitrile charged.

Example 2

284 g (2.5 moles) of cyanoacetic acid ethyl ester, 740 g of orthoformicacid triethyl ester and 10 g of acetic acid anhydride are heated in theflask to ebullition with vigorous stirring. In the course of thereaction approximately 20 g of additional acetic acid anhydride isintroduced. The ethanol that forms during the reaction is distilled outthrough the top ofthe column, the sump temperature rising from 130° to150° C.

After about 4 hours the reaction has ended. The unreacted orthoformicacid triethyl ester is distilled out through the top of the column atreduced pressure and recycled to the next batch. Then ethoxymethylenecyanoacetic acid ethyl ester is separated from the residue through asimple distillation bridge at 0.1 to 0.2 Torr. The yield, with respectto cyanoacetic acid ethyl ester, amounts to 93% of the theory.

Example 3

284 g (2.5 moles) of cyanoacetic acid ethyl ester, 1110 g (7.5 moles) oforthoformic acid triethyl ester and 10 g of acetic acid anhydride arebrought to ebullition in a flask with vigorous stirring. During thereaction, approximately 20 g of additional acetic acid anhydride is fedin, and the ethanol that forms is removed by distillation. The reactionends in 31/2 hours. The unreacted orthoformic acid triethyl ester isdistilled out through the top of the column at reduced pressure (5 to 15Torr). In the fine vacuum, 397 g of ethoxymethylene cyanoacetic acidethylester is distilled out through a distillation bridge at about 0.3Torr. This corresponds to a yield of 94% of the theory, with respect tocyanoacetic acid ethyl ester.

Example 4

284 g (2.5 moles) of cyanoacetic acid ethyl ester, 1110 g (7.5 moles) oforthoformic acid triethyl ester and 8 g of acetic anhydride are heatedat ebullition in a flask with vigorous stirring. During the reaction, 23g ofadditional acetic acid is fed in, and the ethanol that forms isdistilled out. After 3 to 4 hours the reaction has ended.

The unreacted orthoformic acid triethyl ester is removed by distillationthrough the top of the column at reduced pressure (5 to 15 Torr) andrecycled to the next batch. Then, 390 g of ethoxymethylene cyanoaceticacid ethyl ester is evaporated from the residue at 0.05 to 0.2 Torrthrough a simple distillation bridge. The yield is 92% of the theorywith respect to cyanoacetic acid ethyl ester. Melting point, 53° C.

Example 5

284 g of cyanoacetic acid ethyl ester (2.5 moles), 740 g of orthoformicacid triethyl ester (5 moles) and 10 g of propionic acid are brought toebullition in a flask with vigorous stirring. During the reaction 25 gof additional propionic acid is fed in and the ethanol that forms isdistilled out. After about 3 hours the reaction has ended.

The unreacted orthoformic acid triethyl ester is distilled out atreduced pressure (2 to 15 Torr) through the top of the column, and isrecycled to the next batch. Then 380 g of ethoxymethylene cyanoaceticacid ethyl esteris evaporated from the remainder at 0.05 to 0.2 Torrthrough a simple distillation bridge. The yield is 90% of the theorywith respect to cyanoacetic acid ethyl ester. Melting point 51° C.

Example 6

284 g (2.5 moles) of cyanoacetic acid ethyl ester, 1100 g (7.5 moles) oforthoformic acid triethyl ester and 10 g of p-toluenesulfonic acid areheated at ebullition in a flask with vigorous stirring. During thereaction, 25 g of additional acid is fed in in portions, and the ethanolthat forms in the reaction is removed by distillation. After about 4hoursthe reaction has ended.

The unreacted orthoformic acid triethyl ester is distilled off through acolumn at reduced pressure. In the fine vacuum, 360 g of ethoxymethylenecyanoacetic acid ethyl ester is distilled out at about 0.2 Torr througha distillation bridge. This corresponds to a yield of 85% of the theorywithrespect to cyanoacetic acid ethyl ester. Melting point 50° to 51° C.

Example 7

284 g (2.5 moles) of cyanoacetic acid ethyl ester, 740 g (5 moles) oforthoformic acid triethyl ester and 0.5 g of sodium methylate arebrought to ebullition in a flask with vigorous stirring. The alcoholthat forms inthe reaction is distilled out through a column. 31/2 hourslater the reaction has ended. The product is worked up as described inExample 1. The yield is 88% of the theory with respect to cyanoaceticacid ethyl ester. Melting point 50° to 51° C.

Example 8

284 g (2.5 moles) of cyanoacetic acid ethyl ester, 740 g (5 moles) oforthoformic acid triethyl ester and 5 g of triethanolamine are heated atebullition in a flask with vigorous stirring. The alcohol that forms inthe reaction is distilled out through a column. After 4 hours thereactionhas ended. The product is worked up as described in Example 1.The yield is80% of the theory with respect to cyanoacetic acid ethylester. Melting point 50° C.

Example 9

284 g (2.5 moles) of cyanoacetic acid methyl ester, 530 g (5 moles) oforthoformic acid trimethyl ester and 6 g of acetic acid anhydride areheated at ebullition in a flask with vigorous stirring. During thereaction, 25 g of additional acetic acid anhydride is charged and themethanol that forms is distilled out. After 3 hours the reaction hasended.

The unreacted orthoformic acid trimethyl ester is distilled out throughthetop of a column and recycled to the next batch. Then 332 g ofmethoxymethylene cyanoacetic acid is distilled out through a simpledistillation bridge. The yield amounts to 94% of the theory with respectto cyanoacetic acid methyl ester. Melting point 97° C.

Example 10 Ethoxymethylene acetylacetone

253 g (2.5 moles) of acetylacetone, 1,110 g (7.5 moles) of orthoformicacidtriethyl ester and 8 g of acetic anhydride are heated to ebullitionin a flask with vigorous stirring. During the reaction, about 23 g ofacetic acid is added and the ethanol formed is distilled off. After 2 to3 hours the reaction is completed. The unreacted orthoformic acidtriethyl ester is distilled out at reduced pressure (5 to 1 Torr)through the top of the column and fed back to the next batch. Followingthis, 355 g of ethoxymethylene acetylacetone is evaporated, separatedfrom the residue through a simple distillation bridge at 0.1 to 0.3Torr. The yield, referred to acetylacetone, was 91% of theory.

Example 11 Ethoxymethylene acetoacetic acid ethyl ester

A two-liter four-neck flask provided with stirrer, column and droppingfunnel is charged with 1132 g (9 moles) of orthoformic acid triethylester, 390 g (3 moles) of acetoacetic acid ethyl ester and 18 g ofacetic anhydride. The solution is heated to ebullition with vigorousstirring. At130° C. sump temperature, alcohol begins to distill outthrough the top of the column. During the course of the reactionapproximately 32 g ofacetic anhydride is added dropwise. The heating ofthe reaction solution and the reflux flow are regulated so that thetemperatures at the top of the column are between 70° to 79° C. Thecondensed distillate is collected and consists substantially of ethanol,acetic acidethyl ester, formic acid ethyl ester and a small amount oforthoformic acidtriethyl ester. During the reaction the sump temperaturerises slowly to 130° to 140° C. The reaction is completed after 2 to 3hours. The unreacted orthoformic acid triethyl ester is distilled outthrough the column at 2 to 20 Torr and is fed back to the next batch.Ethoxymethylene acetoacetic ester is then evaporated/separated from theresidue at 0.1 Torr through a simple distillation bridge. In thismanner, 520 g of ethoxymethylene acetoacetic ester of a purity of <99%is obtained. This corresponds to a yield of ˜93%, referred to theacetoacetic acid ethyl ester charged. ##STR2##

Comparative Example

66 g (1 mol) malonic dinitrile, 220 g (1.5 mol) orthoformic acidtri-ethylester and 6 g acetic acid anhydride are heated, while stirringvigorously, to ebullition in a flask. During the reaction, approximately6g acetic acid anhydride is added continuously. The alcohol and theformic acid ester developing during the reaction are distilled outthrough the top of the column, while the sump temperature rises from130° to 150° C.

After approximately 2 hours, the reaction is completed. At reducedpressure, the unreacted orthoformic triethyl ester is distilled offthrough the top of the column. Subsequently, 108 g ethoxymethylenemalonicdinitrile, i.e., 88.5% of theory with respect to malonicdinitrile, with a content of 97% is evaporated from the remainder. Afterthe recrystallization from ethanol, the product obtained had a purity of99.3%according to GC analysis.

What is claimed is:
 1. In a process for the preparation of analkoxymethylene malonic acid derivative which comprises contacting acompound selected from the group consisting of ##STR3## wherein R¹ is C₁to C₃ alkyl, andR² is methyl or ethylwith an orthoformic acid trialkylester in the presence of a catalyst at a temperature of 80° to 165° C.,the improvement residing in employing at least 1.6 moles of orthoformicacid ester per mole of said compound and carrying out the process in thepresence of Lewis acid free catalyst consisting essentially of ananhydride of an aliphatic carboxylic acid of 2 to 4 carbon atoms, saidanhydride in an amount of up to 50% of the total amount of anhydride tobe employed being added to the reaction mixture before commencement ofthe reaction and the balance of the anhydride being added during thereaction continuously or in several portions, the alcohol being formedbeing removed during the process.
 2. In a process for the preparation ofan alkoxymethylene malonic acid derivative by reaction of a compoundselected from the group consisting of ##STR4## wherein R¹ is C₁ to C₃alkyl, andR² is methyl or ethylwith an orthoformic acid trialkyl esterhaving 1 to 3 carbon atoms in the alkyl group in the presence of acatalyst, the improvement which comprises employing 1.6 to 6 moles oforthoformic acid ester per mole of said compound and performing theprocess at a temperature between 80° and 165° C. in the presence of aneffective amount of up to 0.5 mole per mole of said compound of a Lewisacid free catalyst consisting essentially of an anhydride of analiphatic carboxylic acid of 2 to 4 carbon atoms, a portion of saidanhydride in an amount of up to 50% of the total amount of anhydride tobe employed being introduced to the reaction vessel before commencementof the reaction and the balance of the anhydride being added to thereaction mixture during the reaction continuously or in severalportions, the alcohol being formed being removed during the process. 3.A process according to claim 1 wherein the compound reacted with theorthoformic acid trialkyl ester has the formula ##STR5##
 4. A processaccording to claim 1 wherein the compound which is reacted with theorthoformic acid trialkyl ester has the formula ##STR6##
 5. A processaccording to claim 1 wherein the compound which is reacted with theorthoformic acid trialkyl ester has the formula ##STR7##
 6. A processaccording to claim 1 wherein the orthoformic acid trialkyl ester isreacted with a compound of the formula ##STR8##
 7. A process accordingto claim 1 wherein the mole ratio of the compound reacted withorthoformic acid trialkyl ester to orthoformic acid ester is between1:1.6 and 1:6.
 8. A process according to claim 1 wherein said anhydrideof an aliphatic carboxylic acid is employed in an amount of at least0.03 mole per mole of compound reacted with the orthoformic acidtrialkyl ester.
 9. A process according to claim 1 wherein the anhydridecatalyst is acetic anhydride.
 10. A process according to claim 2 whereinsaid anhydride is acetic anhydride.
 11. A process according to claim 1wherein said orthoformic acid trialkyl ester has 1 to 3 carbon atoms inthe alkyl group of the ester portion.
 12. A process according to claim 1wherein the alcohol is removed distillatively.
 13. A process accordingto claim 2 wherein the alcohol is removed distillatively.